Stress ulcer susceptibility and depression in Wistar Kyoto (WKY) rats

In a series of studies, Wistar Kyoto (WKY) normotensive rats were more susceptible to water-restraint-induced stress ulcer as compared to spontaneously hypertensive rats (SHR) Fisher-344 (F344) and Wistar rats. In these same studies, WKY rats were also deficient in several behavioral tasks. The four strains were observed in the open-field test of emotionality and WKYs were judged more emotional. In a study on "learned helplessness" WKYs were more deficient in the acquisition of a shuttlebox escape response following unavoidable shock the day before. The prevalence of freezing behavior in the shuttlebox task and the low ambulation scores in the open-field test suggested depressive behavior as a WKY behavior characteristic. WKY rats were judged more depressed in the Porsolt forced-swim test as compared to the other strains. A possible depression-ulcer relationship may exist in WKY rats. This strain may represent a good model for studying possible relationships between depression and stress-induced disease.     

The performance of WKY rats on three tests of emotional behavior.

The behavior of Wistar, Fischer-344, and WKY male rats was observed on three tests of emotional behavior. These included the defensive-withdrawal test, the elevated plus maze, and the conditioned defensive-burying test. Rats were subsequently exposed to the water-restraint ulcerogenic procedure. Fischer-344 rats were more active in the defensive-withdrawal tests, but other behavioral measures in this test did not discriminate between the three strains. Scores reflecting anxiety in the elevated plus maze were lowest for Fischer-344 rats and highest for WKY rats, but the anxiety scores of WKY rats did not differ significantly from Wistar rats. The behavior of WKY rats was significantly different from the other two strains in the conditioned defensive burying test. While the degree of anxiety is measured by burying behavior, elicited by the novelty of prod shock, immobility was the prevalent response of WKY rats. WKY rats also revealed significantly higher ulcer severity scores when exposed to water-restraint stress after each behavioral test procedure. We propose that WKY rats are hyperresponsive to stress and that novelty stress elicits depression-like behavior, which is the prevalent behavioral stress response in WKY rats.     

Interaction between blood pressure quantitative trait loci in rats in which trait variation at chromosome 1 is conditional upon a specific allele at chromosome 10

We have used inbred and congenic rat strains in F(2) segregation studies to discover epistasis in a polygenic model of hypertension. Previously, we have found evidence that the presence of a blood pressure quantitative trait locus (QTL) on chromosome 1 is conditional upon the allele status of chromosome 10. To prove the existence of an epistatic interaction we have analyzed congenic strains for chromosome 1 and 10 carrying high blood pressure QTL alleles from the spontaneously hypertensive rat on a normotensive background of the Wistar-Kyoto (WKY) rat. Additionally, a double congenic strain was developed with both chromosome 1 and 10 high blood pressure QTL alleles on the WKY background. Analysis of variance for blood pressure phenotypes as determined by radiotelemetry showed a significant effect for chromosome 10 but not chromosome 1 QTL alleles and demonstrated a significant interaction between the two loci (P<0.05). The interaction accounted for 5 mmHg of blood pressure. Thus, the identification of epistasis is critical to the understanding of the quantitative nature of blood pressure genetics.     

Major Growth QTLs in Fowl Are Related to Fearful Behavior: Possible Genetic Links Between Fear Responses and Production Traits in a Red Junglefowl × White Leghorn Intercross

The aim of this work was to study fear responses and their relation to production traits in red junglefowl ( Gallus gallus spp.), White Leghorn ( Gallus domesticus ), and their F2-progeny. Quantitative trait locus (QTL) analyses were performed for behavioral traits to gain information about possible genetic links between fear-related behaviors and production. Four behavioral tests were performed that induce different levels of acute fear (open field [OF], exposure to a novel object, tonic immobility, and restraint). Production traits, that is, egg production, sexual maturity (in females), food intake, and growth, were measured individually. A genome scan using 105 microsatellite markers was carried out to identify QTLs controlling the traits studied. In the OF and novel object tests (NO), Leghorns showed less fear behavior than junglefowl, whereas junglefowl behaved less fearfully in the tonic immobility test (TI) and were more active in the restraint test. In the F2 progeny, only weak phenotypic associations were found between production traits and fear behavior. A significant QTL for TI duration was found on chromosome 1 that coincided with a QTL for egg weight and growth in the same animals. Another QTL for NO in males coincided with another major growth QTL. These two known growth QTLs affected a wide range of reactions in different tests. Several other significant and suggestive QTLs for behavioral traits related to fear were found. These QTLs did not coincide with QTLs for production traits, indicating that these fear variables may not be genetically linked to the production traits we measured here. The results show that loci affecting important production traits are located in the same chromosomal region as loci affecting different fear-related behaviors.     

Resolving the composite trait of hypertension into its pharmacogenetic determinants by acute pharmacological modulation of blood pressure regulatory systems

Acute pharmacogenetic analysis was carried out in an intercross F2 population derived from Prague hypertensive-hypertriglyceridemic and Lewis rats. Quantitative trait loci (QTL) mapping was performed for baseline blood pressure (BP) and for BP after blockade of the renin-angiotensin system by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide system by N(G)-nitro- L-arginine methyl ester. Two significant loci for baseline BP were found on chromosome (Chr) 3 (logarithm of likelihood, LOD, 3.8) and Chr 5 (LOD 3.6), and one suggestive locus on Chr 1 (LOD 2.7). The QTL on Chr 3 persisted after treatment with the three agents while the QTL on Chr 5 and Chr 1 disappeared after pentolinium administration. This suggests independence of the locus on Chr 3 from each acute BP regulatory system examined, whereas the loci on Chr 5 and Chr 1 appeared to be controlled mainly by the SNS. Although not apparent at baseline, a significant locus appeared on Chr 8 (LOD 7.0) after blockade of the SNS, and NO system blockade led to the appearance of a new QTL on Chr 1 (LOD 3.6), indicating the contribution of the inhibited systems to these loci. Pharmacogenetic dissection of the BP trait is a powerful tool to unravel the underlying physiological mechanisms of QTL affecting baseline BP and to identify specific QTL for the response to drugs. This pharmocogenetic approach enabled us to determine the main causative acute BP regulatory systems and should lead to better selection of suitable antihypertensive drugs for individual patients.     

A global search reveals epistatic interaction between QTL for early growth in the chicken

We have identified quantitative trait loci (QTL) explaining a large proportion of the variation in body weights at different ages and growth between chronological ages in an F(2) intercross between red junglefowl and White Leghorn chickens. QTL were mapped using forward selection for loci with significant marginal genetic effects and with a simultaneous search for epistatic QTL pairs. We found 22 significant loci contributing to these traits, nine of these were only found by the simultaneous two-dimensional search, which demonstrates the power of this approach for detecting loci affecting complex traits. We have also estimated the relative contribution of additive, dominance, and epistasis effects to growth and the contribution of epistasis was more pronounced prior to 46 days of age, whereas additive genetic effects explained the major portion of the genetic variance later in life. Several of the detected loci affected either early or late growth but not both. Very few loci affected the entire growth process, which points out that early and late growth, at least to some extent, have different genetic regulation.     

A resource for the simultaneous high-resolution mapping of multiple quantitative trait loci in rats: the NIH heterogeneous stock

The laboratory rat (Rattus norvegicus) is a key tool for the study of medicine and pharmacology for human health. A large database of phenotypes for integrated fields such as cardiovascular, neuroscience, and exercise physiology exists in the literature. However, the molecular characterization of the genetic loci that give rise to variation in these traits has proven to be difficult. Here we show how one obstacle to progress, the fine-mapping of quantitative trait loci (QTL), can be overcome by using an outbred population of rats. By use of a genetically heterogeneous stock of rats, we map a locus contributing to variation in a fear-related measure (two-way active avoidance in the shuttle box) to a region on chromosome 5 containing nine genes. By establishing a protocol measuring multiple phenotypes including immunology, neuroinflammation, and hematology, as well as cardiovascular, metabolic, and behavioral traits, we establish the rat HS as a new resource for the fine-mapping of QTLs contributing to variation in complex traits of biomedical relevance.     

Strain, age, but not gender, influence ulcer severity induced by water-restraint stress

Two ulcerogenic procedures, supine restraint (SR) and water restraint (WR) were compared. In Experiment 1, Fischer-344 (F344), Sprague-Dawley (S-D), Wistar, Long-Evans (L-E), Spontaneously Hypertensive rats (SHR) and Wistar Kyoto normotensive (WKY) rats were exposed to SR and WR. WR produced more ulcers than SR. There was no difference in ulcer scores between WKY, F344 and L-E but these rats had significantly more ulcers as compared to SHR, Wistar and S-D rats. In Experiment 2, 4- and 16-month-old SHR, WKY and F344 rats were exposed to SR and WR. The older WKY rats had more ulcers than all other treatment groups. Experiment 3 revealed no significant differences between male and female rats exposed to either SR or WR. Body temperature (BT) scores obtained after restraint and after 2-hr postrestraint rest were only marginally related to ulcer severity. Rats exposed to WR had lower BT scores but the strain and age ulcer differences did not have corresponding BT differences. These studies revealed the following: the ulcer susceptibility of WKY rats; the WR technique is a useful ulcerogenic procedure; and hypothermia is a weak covariant to restraint-induced stress ulcer.     

Identification of multiple genetic loci linked to the propensity for "behavioral despair" in mice

The forced swim test (FST) and tail suspension test (TST) are widely used and well established screening paradigms for antidepressants. A variety of antidepressive agents are known to reduce immobility time in both FST and TST. To identify genetic determinants of immobility duration in both tests, we analyzed 560 F2 mice from an intercross between C57BL/6 (B6) and C3H/He (C3) strains. Composite interval mapping revealed five major loci (suggestive and significant linkage) affecting immobility in the FST, and four loci for the TST. The quantitative trait loci (QTL) on chromosomes 8 and 11 overlap between the two behavioral measures. Genome-wide interaction analysis, which was developed to identify locus pairs that may contribute epistatically to a phenotype, detected two pairs of chromosomal loci for the TST. The QTL on chromosome 11 and its associated epistatic TST-QTL on chromosome X encode gamma-aminobutyric acid type A (GABA(A)) receptor subunits as candidates. Sequence and expression analyses of these genes from the two parental strains revealed a significantly lower expression of the alpha1 subunit gene in the frontal cortex of B6 mice compared to C3 mice. The present quantitative trait study should open up avenues for identifying novel molecular targets for antidepressants and unraveling the complex genetic mechanisms of depressive and anxiety disorders.     

Mapping Quantitative Trait Loci for Open-Field Behavior in Mice

By performing a whole genome screen in an F₂ intercross of two strains of mice (A/J and C57BL/6J), which differ markedly in their behavioral response to a brightly lit open field (O-F), we have mapped several quantitative trait loci (QTL) for this complex behavioral phenotype. QTL on chromosomes 1 and 10 were identified that affect both initial ambulation in the O-F (initial response to novelty ambulation) (lod of 7.1 and 8.8, respectively) and vertical rearings (lod of 4.5 and 8.5, respectively). For habituated O-F behavior, QTL were identified on chromosomes 3 and 10 for ambulation (lod of 4.1 and 14.7, respectively) and on chromosomes 1, 10, and 19 for vertical rearings (lod of 5.8, 6.0, and 4.7, respectively). The QTL on chromosome 1 (near D1Mit1 16; 101 cM) was specific for initial O-F ambulation behavior, whereas the QTL on chromosome 10 (near D10Mit237; 74 cM) affected both initial and habituated rearing behavior. Additional suggestive QTL (lod, >2.8) were mapped to chromosomes 1, 8, 11, 15, and 19. The QTL on chromosomes 1, 10, and 19 individually explain from 3.2 to 12.7%. Collectively, the multiple independent QTL explain from 16.3 to 24.1% of the F₂ population's phe-notypic variance, depending on the trait. These identified QTL should prove useful for dissecting the genetic and behavioral dimensions of O-F behavior, fostering an understanding of individual differences.     

Quantitative trait loci affecting natural variation in Drosophila longevity

Limited life span and senescence are universal phenomena, controlled by genetic and environmental factors whose interactions both limit life span and generate variation in life span between individuals, populations and species. To understand the genetic architecture of longevity it is necessary to know what loci affect variation in life span, what are the allelic effects at these loci and what molecular polymorphisms define quantitative trait locus (QTL) alleles. Here, we used quantitative complementation tests to determine whether genes that regulate longevity also contribute to naturally occurring variation in Drosophila life span. Inbred strains derived from a natural population were crossed to stocks containing null mutations (m) or deficiencies (Df) uncovering the candidate genes, maintained over a Balancer (Bal) chromosome. We measured the life span of the resulting F(1) genotypes, +(i)/m (Df) and +(i)/Bal, where +(i) denotes one of the i natural alleles. Failure of the QTL alleles to complement the candidate gene mutation is indicated by a significant cross (mutant versus wild-type allele of the candidate gene) by inbred line interaction term from analysis of variance of life span. Failure to complement indicates a genetic interaction between the candidate gene allele and the naturally occurring life span QTL, and implicates the candidate gene as potential cause of variation in longevity. Of the 16 candidate regions and genes tested, Df(2L)c17, Df(3L)Ly, Df(3L)AC1 and Df(3R)e-BS2 showed significant failure to complement wild-type alleles in both sexes, and an Alcohol dehydrogenase mutant failed to complement in females. Several genes that regulate life span (e.g., Superoxide dismutase, Catalase, and rosy) complemented the life span effects of wild-derived alleles, suggesting little natural variation affecting longevity at these loci, at least in this sample of alleles. Quantitative complementation tests are therefore useful for identifying QTL contributing to segregating genetic variation in life span in nature.     

Induction of FOS expression by acute immobilization stress is reduced in locus coeruleus and medial amygdala of Wistar-Kyoto rats compared to Sprague-Dawley rats

Activation of the brain noradrenergic system during acute stress is thought to play an important integrative function in coping and stress adaptation by facilitating transmission in many brain regions involved in regulating behavioral and physiologic components of the stress response. Compared with outbred control Sprague-Dawley (SD) rats, inbred Wistar-Kyoto (WKY) rats exhibit an exaggerated hypothalamic-pituitary-adrenal (HPA) response as well as increased susceptibility to certain forms of stress-related pathology. However, we have also shown previously that WKY rats exhibit reduced anxiety-like behavioral reactivity to acute stress, associated with reduced activation of the brain noradrenergic system. Thus, to understand better the possible neurobiological mechanisms underlying dysregulation of the stress response in WKY rats, we investigated potential strain differences in stress-induced neuronal activation in brain regions that are both involved in regulating behavioral and neuroendocrine stress responses, and are related to the noradrenergic system, either as targets of noradrenergic modulation or as sources of afferent innervation of noradrenergic neurons. This was accomplished by visualizing stress-induced expression of Fos immunoreactivity in the paraventricular nucleus of the hypothalamus, lateral bed nucleus of the stria terminalis, central nucleus of the amygdala, and medial nucleus of the amygdala (MeA), as well as the noradrenergic nucleus locus coeruleus (LC). Stress-induced Fos expression was found to be decreased in the LC and MeA of WKY rats compared with similarly stressed SD rats, whereas no strain differences were observed in any of the other brain regions. This suggests that strain-related differences in activation of the MeA may be involved in the abnormal neuroendocrine and behavioral stress responses exhibited by WKY rats. Moreover, as the MeA is both an afferent as well as an efferent target of the brainstem noradrenergic system, reduced MeA activation may either be a source of reduced noradrenergic reactivity seen in WKY rats, or possibly a consequence. Nonetheless, understanding the mechanisms underlying altered stress reactivity in models such as the WKY rat may contribute to a better understanding of stress-related psychopathologies such as depression, post-traumatic stress disorder or other anxiety disorders.     

Genetic verification of the role of CCK-AR in pancreatic proliferation and blood glucose and insulin regulation using a congenic rat carrying CCK-AR null allele

A number of studies have indicated that cholecystokinin type A receptor (CCK-AR) plays a crucial role in postnatal pancreatic proliferation and blood glucose regulation through stimulating insulin secretion. The Otsuka Long-Evans Tokushima Fatty (OLETF) rat has been shown to possess poor pancreatic proliferation (PPP) capability after pancreatectomy (Px). Here we have constructed a congenic strain which introgressed an OLETF-derived 18.5 cM genomic fragment identified in our previous quantitative trait locus (QTL) analysis as a locus responsible for PPP into normoglycemic F344 genetic background The introgressed region includes CCK-AR null mutation. After Px, the congenic rat showed weak pancreatic proliferation equivalent to that of the OLETF rat. Furthermore, post-surgery non-fasting blood glucose levels for the congenic rats are significantly higher in comparison with the F344 rats. At 28 days after Px, the congenic rats also showed lower blood insulin levels than the F344 rats. These results further provide the genetic evidence that 1) CCK-AR is essential for pancreatic regeneration; 2) impaired pancreatic proliferation mediates the development of hyperglycemia.     

Mapping of QTL Influencing Saccharin Consumption in the Selectively Bred Alcohol-Preferring and -Nonpreferring Rat Lines

The inbred preferring (iP) and nonpreferring (iNP) rat strains were derived from the selectively bred alcohol-preferring (P) and alcohol-nonpreferring (NP) lines. Previously, 381 iP × iNP F2 progeny were generated to identify quantitative trait loci (QTLs) influencing alcohol consumption and preference. Saccharin consumption (ml/48 h) and saccharin intake (ml/kg/day) were also measured in the F2 sample and were significantly correlated with both alcohol consumption and preference (all r .20, p < .0001), suggesting that there might be some QTLs influencing both saccharin and alcohol phenotypes. We have performed a genome screen using F2 animals with extreme saccharin or alcohol consumption to identify QTLs contributing to saccharin-related phenotypes. Lod scores greater than 2.0 were found on chromosomes 3, 16 and 18 in this sample. Additional genotyping was performed in these regions in the full sample of 381 F2 progeny to further characterize these putative QTLs. On chromosome 3, the maximum lod score in the full sample was 2.7 with saccharin consumption. This QTL appears to overlap with a QTL identified for alcohol consumption in the iP and iNP lines and has pleiotropic effects on both phenotypes. Interestingly, this region of rat chromosome 3 is syntenic with mouse chromosome 2, where a QTL influencing alcohol preference has been previously reported. The QTL on chromosome 16 has a maximum lod score of 4.0 with saccharin intake and 2.6 with saccharin consumption. The QTL on chromosome 18 has a maximum lod score of 2.7 with saccharin consumption. Taken together, these data provide the first results of a genome screen for QTLs contributing to saccharin phenotypes in the rat.     

A quantitative trait locus influencing anxiety in the laboratory rat

A critical test for a gene that influences susceptibility to fear in animals is that it should have a consistent pattern of effects across a broad range of conditioned and unconditioned models of anxiety. Despite many years of research, definitive evidence that genetic effects operate in this way is lacking. The limited behavioral test regimes so far used in genetic mapping experiments and the lack of suitable multivariate methodologies have made it impossible to determine whether the quantitative trait loci (QTL) detected to date specifically influence fear-related traits. Here we report the first multivariate analysis to explore the genetic architecture of rodent behavior in a battery of animal models of anxiety. We have mapped QTLs in an F2 intercross of two rat strains, the Roman high and low avoidance rats, that have been selectively bred for differential response to fear. Multivariate analyses show that one locus, on rat chromosome 5, influences behavior in different models of anxiety. The QTL influences two-way active avoidance, conditioned fear, elevated plus maze, and open field activity but not acoustic startle response or defecation in a novel environment. The direction of effects of the QTL alleles and a coincidence between the behavioral profiles of anxiolytic drug and genetic action are consistent with the QTL containing at least one gene with a pleiotropic action on fear responses. As the neural basis of fear is conserved across species, we suggest that the QTL may have relevance to trait anxiety in humans.     

Use of A Standard Strain for External Calibration in Behavioral Phenotyping

The present paper evaluates the inclusion of a standard strain or outbred stock in multi-strain behavioral phenotyping protocols to perform the same role as the external standard in biochemical assay procedures. As potential standards, the F344 inbred strain and an outbred stock of Long Evans were tested with three other inbred strains. To evaluate the influence of rearing conditions on phenotype stability, one group of F344s was born at the University of Tsukuba, another, bred elsewhere and delivered to Tsukuba at 4 weeks of age. All animals were tested in open-field (OF), runway emergence (RE) and digging tests as adults. The results showed no influence of breeding or transportation history on OF and RE behavior of the two F344 groups, while there was evidence that digging behavior may be affected by the different rearing experience. The inclusion of a standard strain or stock in phenotyping protocols involving multiple inbred strains or lines of rats, mice and flies has obvious advantages by providing a reference point for inter-laboratory comparisons. The properties of inbred strains and outbred stocks favorable to their use as standards are discussed.     

Effects of Cross Fostering on Open-Field Behavior, Acoustic Startle, Lipopolysaccharide-Induced Corticosterone Release, and Body Weight in Lewis and Fischer Rats

Lewis (LEW/N) and Fischer (F344/N) rats differ on a myriad of behavioral and physiological endpoints, some of which have been reported to be affected by maternal experience in outbred rats and other strains. To assess whether epigenetic factors contribute to the differential behavioral responses to stress and pro-inflammatory challenges in these strains, the effects of cross fostering on open-field, acoustic startle, and glucocorticoid reactivity to lipopolysaccharide (LPS) were examined in the present experiment. In the open-field test, although in-fostered female LEW/N and F344/N strains did not differ, female LEW/N rats displayed significantly greater activity than female F344/N rats in the cross-fostered condition. Differences between males of the two strains were increased by cross fostering, with the LEW/N strain displaying greater total activity. In acoustic startle, there was little strain difference between in-fostered or cross-fostered female rats. On the other hand, in-fostered male LEW/N rats had a significantly greater startle response than in-fostered male F344/N rats, an effect that was dramatically reduced by cross fostering. In-fostered female LEW/N rats displayed a blunted corticosterone response relative to in-fostered female F344/N rats, an effect that was reduced by cross fostering. Conversely, although there was no strain difference between male in-fostered rats, cross-fostered male F344/N rats displayed a significantly greater corticosterone response to LPS than cross-fostered male LEW/N rats. Finally, body weight differences between in-fostered LEW/N and F344/N rats were reduced by cross fostering. Together, these data illustrate that maternal factors play a role in the behavioral and physiological responses to stress between the two strains.     

Epistasis in Quantitative Trait Locus Linkage Analysis: Interaction or Main Effect?

This paper explores a two-locus variance components model of quantitative trait locus (QTL) linkage for sib-pairs that incorporates epistasis. For a range of epistatic models the expected variance components and noncentrality parameter per sib-pair can be calculated, to indicate the power to detect epistasis. In QTL linkage analysis, additive and epistatic effects are in fact partially confounded; as a result, variance components under incorrect submodels can be distorted, with two main implications. First, the analysis of a single locus can in fact detect a QTL that has no main effect but interacts epistatically with another (unmeasured) locus. That is, single-locus approaches do not necessarily preclude the detection of purely epistatically interacting loci. Second, because the nonepistatic variance component estimates in submodels can partially absorb epistatic variance when it is not explicitly modeled, power to formally detect epistasis is low.     

Genetic linkage of hyperglycemia, body weight and serum amyloid-P in an intercross between C57BL/6 and C3H apolipoprotein E-deficient mice

Dyslipidemia and hyperglycemia are integral components of the metabolic perturbations in type 2 diabetes. Apolipoprotein E-deficient (apoE(-/-)) mice develop severe hyperlipidemia and significant hyperglycemia when fed a western diet containing 21% fat (w/w), 0.15% cholesterol and 19.5% casein. Using an intercross between C57BL/6J (B6) and C3H/HeJ (C3H) apoE(-/-) mice, we performed quantitative trait locus (QTL) analysis to identify loci contributing to hyperglycemia and associated traits. Fasting plasma levels of glucose, insulin and serum amyloid-P (SAP) and body weight in 234 female F2 mice were measured after being fed the western diet for 12 weeks. QTL analysis revealed one significant QTL, named Bglu3 [95.8 cM, logarithm of odds ratio (OR)(LOD) 4.1], on chromosome 1 and a suggestive QTL on chromosome 9 (38 cM, LOD 2.3) that influenced plasma glucose levels. Bglu3 coincided with loci on distal chromosomal 1 that had a major influence on plasma SAP levels and body weight. Significant correlations between plasma glucose, SAP and body weight were observed in F2 mice. Thus, these results demonstrate genetic linkages of hyperglycemia and body weight with SAP, a marker of the acute-phase response, in hyperlipidemic apoE(-/-) mice and suggest a probability for the Sap gene to be a positional candidate of Bglu3.     

A male-specific quantitative trait locus on 1p21 controlling human stature

Background: Many genome-wide scans aimed at complex traits have been statistically underpowered due to small sample size. Combining data from several genome-wide screens with comparable quantitative phenotype data should improve statistical power for the localisation of genomic regions contributing to these traits. Objective: To perform a genome-wide screen for loci affecting adult stature by combined analysis of four previously performed genome-wide scans. Methods: We developed a web based computer tool, Cartographer, for combining genetic marker maps which positions genetic markers accurately using the July 2003 release of the human genome sequence and the deCODE genetic map. Using Cartographer, we combined the primary genotype data from four genome-wide scans and performed variance components (VC) linkage analyses for human stature on the pooled dataset of 1417 individuals from 277 families and performed VC analyses for males and females separately. Results: We found significant linkage to stature on 1p21 (multipoint LOD score 4.25) and suggestive linkages on 9p24 and 18q21 (multipoint LOD scores 2.57 and 2.39, respectively) in males-only analyses. We also found suggestive linkage to 4q35 and 22q13 (multipoint LOD scores 2.18 and 2.85, respectively) when we analysed both females and males and to 13q12 (multipoint LOD score 2.66) in females-only analyses. Conclusions: We strengthened the evidence for linkage to previously reported quantitative trait loci (QTL) for stature and also found significant evidence of a novel male-specific QTL on 1p21. Further investigation of several interesting candidate genes in this region will help towards characterisation of this first sex-specific locus affecting human stature.